Life Beyond Kinases: Structure-Based Discovery of Sorafenib as Nanomolar Antagonist of 5-HT Receptors

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• 作者：Xingyu Lin ; Xi-Ping Huang ; Gang Chen ; Ryan Whaley ; Shiming Peng ; Yanli Wang ; Guoliang Zhang ; Simon X. Wang ; Shaohui Wang ; Bryan L. Roth ; Niu Huang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 28, 2012
• 年：2012
• 卷：55
• 期：12
• 页码：5749-5759
• 全文大小：506K
• 年卷期：v.55,no.12(June 28, 2012)
• ISSN：1520-4804

文摘

Of great interest in recent years has been computationally predicting the novel polypharmacology of drug molecules. Here, we applied an 鈥渋nduced-fit鈥?protocol to improve the homology models of 5-HT_2A receptor, and we assessed the quality of these models in retrospective virtual screening. Subsequently, we computationally screened the FDA approved drug molecules against the best induced-fit 5-HT_2A models and chose six top scoring hits for experimental assays. Surprisingly, one well-known kinase inhibitor, sorafenib, has shown unexpected promiscuous 5-HTRs binding affinities, K_i = 1959, 56, and 417 nM against 5-HT_2A, 5-HT_2B, and 5-HT_2C, respectively. Our preliminary SAR exploration supports the predicted binding mode and further suggests sorafenib to be a novel lead compound for 5HTR ligand discovery. Although it has been well-known that sorafenib produces anticancer effects through targeting multiple kinases, carefully designed experimental studies are desirable to fully understand whether its 鈥渙ff-target鈥?5-HTR binding activities contribute to its therapeutic efficacy or otherwise undesirable side effects.